Wei Xu, PhD
Position title: Professor, Oncology
Phone: (608) 265-5540
7457 Wi Institute Medical Research
1111 Highland Ave
Madison, WI 53705
- Organ System/Disease Focus
- Mesenchymal stem cell lineage-specific differentiation, osteoporesis
- Aligned Research Focus
- basic stem cell science, tissue engineering of bone
Human mesenchymal stromal cells (hMSC) can differentiate into adipocytes, osteoblasts and chondrocytes, thus have enormous therapeutic potential in regenerative medicine . However, the epigenetic and transcription regulatory mechanism in stem cell fate determination and differentiation requires elucidation . Co-activator associated arginine methyltransferase 1 (CARM1) has emerged as an important epigenetic regulator for pluripotency and differentiation of stem cells . CARM1 catalyzes active histone modification at H3R17. In studying H3R17me2 mediated gene activation mechanism, we discovered that H3R17me2 recruits Ctr9, the scaffold subunit of RNA polymerase II-associated factor complex (PAFc) as “reader” protein . A genome-wide association study identified Ctr9 as a candidate gene involved in osteoporosis in Kashin-Beck disease patients . To study if Ctr9 plays a role in MSC lineage differentiation, we knocked down (KD) Ctr9 in human MSCs followed by induction of multi-lineage differentiation. Our results showed that osteogenic differentiation (OD) was blocked, whereas adipogenic and chondrocyte differentiation were not affected by loss of Ctr9. Restoration of Ctr9 in hMSC rescued OD, and exogenous expression of Ctr9 augments OD, indicating a dose-dependent effect of Ctr9 in promoting OD. Further studies in Xu lab will determine the mechanism by which CARM1-H3R17me2-Ctr9 axis functionally regulates MSC cell lineage differentiation.
- Brooke, G., et al., Therapeutic applications of mesenchymal stromal cells. Semin Cell Dev Biol, 2007. 18(6): p. 846-58.
- Ozkul, Y. and U. Galderisi, The Impact of Epigenetics on Mesenchymal Stem Cell Biology. J Cell Physiol, 2016. 231(11): p. 2393-401.
- Wu, Q., et al., CARM1 is required in embryonic stem cells to maintain pluripotency and resist differentiation. Stem Cells, 2009. 27(11): p. 2637-2645.
- Wu, J. and W. Xu, Histone H3R17me2a mark recruits human RNA polymerase-associated factor 1 complex to activate transcription. Proc Natl Acad Sci U S A, 2012. 109(15): p. 5675-80.
- Wen, Y., et al., Integrative analysis of genome-wide association studies and gene expression profiles identified candidate genes for osteoporosis in Kashin-Beck disease patients. Osteoporos Int, 2016. 27(3): p. 1041-1046.